Evaluation of CYP2C9 and VKORC1 gene variants that may result in warfarin dosage sensitivity and poor pregnancy outcomes

Abstract:

Warfarin is the most widely prescribed oral anticoagulant used for the long-term treatment
and prevention of thromboembolic events. Its administration is challenging as it may result
in bleeding-related deaths, inadequate anticoagulation and fetal teratogenesis, including
fetal warfarin syndrome. A number of environmental and genetic factors contribute to
interindividual warfarin dosage variability. The CYP2C9 and VKORC1 genes explain 40-
50% of this variability. The aim of this study was to determine the frequency of known and
any new variants in these genes in the SA black population, and correlate these variants
and a small subset of environmental factors to dosage variability and pregnancy outcomes.
I sequenced the exons and intron/exon boundaries of the CYP2C9 and VKORC1 genes in
100 random black control and 113 patient samples that had at least one pregnancy on
warfarin. I observed six previously described CYP2C9 variants, 27 novel CYP2C9 variants,
and three previously described VKORC1 variants. 14 of these variants were observed at an
allele frequency of 0.02. Of these 14, six appear to decrease (all of which are CYP2C9
variants) and four increase (2 CYP2C9 variants and two VKORC1 variants) warfarin
dosage requirement. These 14 CYP2C9 and VKORC1 variants along with a small subset of
environmental factors account for 45.3% of warfarin dosage variability in the SA
population. I observed an increase in the number of poor pregnancy outcomes in patients
on high doses of warfarin. These results allow us to predict the maintenance dose of
warfarin in SA black patients better, thereby reducing the risk of adverse effects, and
identify those at risk of having a poor pregnancy outcome.